Multiple myeloma is currently incurable with available treatments. While autologous transplants have been demonstrated to delay disease progression, all patients will ultimately relapse with disease. In contrast, allogeneic transplants have increased the number of patients achieving a complete remission that may result in long-term cures suggestive of a measurable immune-mediated anti-tumor effect. Broader applicability is, however, limited by donor availability and excessive toxicity. To date, we have conducted a vaccine study as well as a trial utilizing autologous peripheral blood lymphocytes (PBLs) activated in vitro with anti-CD3/CD28 beads. The lack of functional effector T cells in the former and the absence of tumor-specificity in the latter studies significantly limited the overall anti-tumor specificity. Marrow infiltrating lymphocytes (MILs) represent a novel approach to isolate and expand T cells from the bone marrow microenvironment in patients with hematologic disorders and they demonstrate greater tumor specificity than is observed with PBLs. These cells recognize and kill myeloma cells more effectively than PBLs. Furthermore, they express surface markers such as CXCR4 thereby increasing their likelihood of trafficking to the marrow upon reinfusion and they possess fewer regulatory T cells than their PBL counterparts. In addition to killing mature, malignant plasma cells, they also recognize the myeloma precursors thereby offering the possibility of inducing long-lasting clinical responses. Lastly, in NOD/SCID experiments we see evidence of trafficking and long-term persistence of MILs in the bone marrow of mice with an associated potent anti-tumor effect. We, thus, propose a clinical study to examine the anti-myeloma efficacy of activated MILs infused following an autologous transplant. The kinetics of immune reconstitution, tumor-specific T cell activity against mature plasma cells in both the peripheral blood as well as marrow will be examined in addition to the parameters of clinical responsiveness. PUBLIC HEALTH RELEVANCE: Multiple myeloma is currently incurable with autologous stem cell transplants which have been used with certain clinical efficacy but are not curative. Immunotherapy can increase the anti-myeloma efficacy of transplants and we have recently shown that bone marrow derived T cells "immune cells" have potent anti-myeloma activity. We will perform a clinical trial utilizing these activated marrow infiltrating lymphocytes in myeloma patients.